The 17(α)-17-acetyl-17-hydroxy-estr-4-en-3-one (hereafter: gestonorone) is an important intermediate in the synthesis of the active ingredients having progestogen activity—such as gestonorone capronate and nomegestrol acetate. There are various known processes in the literature for its synthesis. The first was described in 1953 (MXX762308, U.S. Pat. No. 2,781,365; GB 762,308). In this process the gestonorone was synthesized starting from 17-acetyl-3-hydroxy-estra-1,3,5(10),16-tetraene via a derivative of 17β-acetyl-17α-hydroxy-3-methoxy-estra-1,3,5(10)-triene protected in position 20 with ethylene ketal.
In the U.S. Pat. No. 3,381,003 the gestonorone is synthesized starting from estron-3-alkyl ether (FIG. 1.). The pregnane side-chain in position 17 is synthesized in a complicated and time-consuming 7-step process. The oxo group in position 20 is protected as ethylene ketal, then the necessary transformations are carried out on the A-ring.
The estron-3-alkyl ether is ethynylated in position 17, the 17 hydroxyl group of the obtained compound is acylated and the ethynyl group is brominated with N-bromo-acetamide in an organic solvent in the presence of tert-butanol and water. In the next debromination reaction the 17α-acetyl-3-alkoxy-17β-hydroxy-gona-1,3,5(10)-trien-17β-yl-acetate is formed in the presence of zinc and acetic acid, which is then reduced with calcium metal in liquid ammonia. The isopregnane side-chain of the obtained compound is isomerized in acetic acid in the presence of zinc at reflux temperature for 24 h. The hydroxyl group in position 17 is introduced the following way: the oxo group in position 20 is transformed into enol acetate with acetic anhydride in the presence of catalytic amount of p-toluenesulfonic acid and the formed Δ17(20)-double bond is oxidized with perbenzoic acid. Finally the oxo group in position 20 is transformed into ethylene ketal with ethylene glycol in the presence of catalytic amount of p-toluenesulfonic acid. The next two reaction steps are carried out as described in point 1, the derivative of 17β-acetyl-17α-hydroxy-3-methoxy-estra-1,3,5(10)-triene protected in position 20 with ethylene ketal is reduced with lithium metal in liquid ammonia and the obtained compound is transformed into gestonorone with acid hydrolysis.
According to the U.S. Pat. No. 3,423,435 17-cyano-17-hydroxy-3-methoxy-estra-2,5(10)-diene (a mixture of isomers/diastereomers) is synthesized starting from 3-methoxy-estra-2,5(10)-dien-17-one with acetone cyanohydrin, which is acylated with acetic anhydride in pyridine (FIG. 2.). The synthesis of cyanohydrin is also described starting from 19-nor-androsten-dione.
During the two processes below the 17α-hydroxy-pregnane side-chain is synthesized starting from estr-4-en-3-one or an estr-4-en-3-one derivatives.
In the U.S. Pat. No. 3,764,615 the synthesis of the 17α-hydroxy-pregnane derivatives is described (FIG. 3.). The pregnane side-chain is synthesized via the sulfite ester derivatives of 17α-ethynyl-17β-hydroxy steroids the following way: the ethynyl group is transformed into pregnane side-chain via hydration in the presence of mercury salt. The disadvantage of the process is the use of environmental pollutant mercury salt.
In the Chinese article published in Journal of Central South University of Technology (English Edition) (2004), 11(3), 300-303 estr-4-en-3-on-17-cyanohydrine is synthesized from estr-4-en-3,17-dione with potassium cyanide in aqueous methanol, then the oxo group of the obtained product is protected as ketal using ethylene glycol and boron trifluoride as catalyst. The tertiary hydroxy! group is protected with butyl vinyl ether and the pregnane side-chain is formed with methyl lithium in diethyl ether as solvent. The protective groups are removed with hydrochloric acid hydrolysis. The overall yield of the six-step process is 63% (FIG. 4.).